THE  SYNTHESIS  OF  DIVARIN 


BY 


CLIFFORD  FRED  RASSWEILER 
A.  B.  University  of  Denver  1920. 


THESIS 

Submitted  in  Partial  Fulfillment  of  the  Requirements  for  the 

Degree  of 


MASTER  OF  SCIENCE 
IN  CHEMISTRY 

IN 

THE  GRADUATE  SCHOOL 

OF  THE 


UNIVERSITY  OF  ILLINOIS 


1922 


UNIVERSITY  OF  ILLINOIS 


THE  GRADUATE  SCHOOL 


January  19  ^ 


I HEREBY  RECOMMEND  THAT  THE  THESIS  PREPARED  UNDER  MY 


SUPERVISION  BY Clifford  Ered  Hcmsweiler 


ENTITLED 


THE  SYNTHESIS  OH  D I VAR IN 


BE  ACCEPTED  AS  FULFILLING  THIS  PART  OF  THE  REQUIREMENTS  FOR 


THE  DEGREE  OF 


MASTER  OH  SCIENCE 


Recommendation  concurred  in* 


Committee 

on 

Final  Examination* 


Required  for  doctor’s  degree  but  not  for  master’s 


Digitized  by  the  Internet  Archive 
in  2015 


https://archive.org/details/synthesisofdivarOOrass 


THE  SYNTHESIS  OP  DIVAHIH 


Clifford  F.  Rassweiler 


I wish  to  take  this  opportunity 
to  thank  Professor  Roger  Adams  for 
the  suggestion  of  this  problem  and 
for  the  advice  ne  has  given  durixig 
the  caur  se  of  the  work. 


TABLE  0 F CONTENTS 


I INTRODUCTION  1 

II  HISTORICAL  2 

III  THEORETICAL  4 

A.  Preparation  of  a symmetrical  dihydroxy 

benzene  derivative  4 

B.  Conversion  of  the  preceding  into 

divarin  8 

IV  EXPERIMENTAL  10 

A.  Triethyl  orcin  tricar boxy late  10 

B.  3, 5 > Li hydroxy  phenyl  acetic  acid  11 

C.  3> 5 , Limethoxy  phenyl  acetic  acid.  12 

V CONCLUSIONS  14 

VI  BIBLIOGRAPHY  13 


THE  SYNTHESIS  OF  DIVARIN 
I INTRODUCTION 

Divarin  is  a dihydroxy  propyl  benzene  of  the  empirical 
formula  C9H12O2,  secured  by  the  action  of  alkalis  ana 
hydriodic  acid  on  certain  complex  acids  extracted  from  the 
lichen  Evernia  illyrica. 

This  research  was  undertaken  with  the  object  of  syn- 
thesizing divarin  oy  such  means  as  to  ijrove  the  structural 
f ormula  sugg  ested  by  Ilesse.  This  structure  is  at  present 
subject  to  considerable  dispute. 


-2- 


II  HISTORICAL 

Divarin  was  first  definitely  identified  and  cnaracter- 

1 3 

ized  oy  0.  Hesse  in  1910.  although  Zopf  probably  had  some 

of  the  compound  in  impure  form  before  that  time.  Hesse 

extracted  divaricatic  acid  (C31H34Q7)  from  the  lichen 

Ever nia  illyrica.  This  divaricatic  acid  on  treatment  with 

alkali  and  hyair iodic  acid  yields  a dihydroxy  phenol  of  the 

empirical  formula  C9K13O3  to  which  the  name  divarin  is 

given.  Hesse  found  the  melting  point  of  the  hydrate  to 
o 0 

be  44  and  trie  anhydrous  form  82  . To  this  compound  Hesse 
assigned  the  formula  3 > 3 > dihydrocy  I,  11-propyl  benzene  (I) 
largely  because  of  its  marked  resemblance  to  orcin  (II) 
both  in  occurrence  and  properties* 


CH3CH2 CHs 

A 

OH.  \J  OK 


CHa 

A 

0iV0H 


1 


11 


3 

Johnson  and  Hodge  have  prepared  2,4, dihydroxy  I,n- 

propyl  benzene  and  found  its  anhydrous  form  to  melt  at  82°- 
o 0 

03  . This  melting  point  agrees  with  that  found  by  Hesse  for 
anhydrous  divarin.  The  description  of  the  2,4  compound  was 
too  orief , however,  to  make  the  identification  certain  so 

4 

the  work  of  Johnson  and  Hodge  was  repeated  by  Adolf  Som*. 


-3- 

He  found  that  the  anhydrous  2, 4, dihydroxy  propyl  benzene  thus 

0 ' Q 

prepared  melted  at  IP?  -10o  while  tl  Lydrated  or m 

melting  point  of  71u.  He  concluded  that  the  compound  describe 

ed  by  Johnson  was  a mixture  of  the  two  forms  and  that  the 

2,4  phenol  was  not  identical  with  divarin. 

At  present  the  original  structural  formula  proposed  oy 

Hesse  is  generally  accepted  though  not  definitely  proved. 

Ho  attempts  to  prepare  divarin  synthetically  have  seen 

reported  in  the  literature.  Its  monomethyl  and  dimethyl 

ethers  have  been  prepared  however  from  complex  plant  pro- 
fs 

ducts . 


-4- 

III  THEORETICAL 

The  chief  difficulty  to  be  overcome  in  this  synthesis  is 
in  placing  the  two  hydroxyl  groups  in  a symmetrical  position 
with  regard  to  the  propyl  side  chain.  The  synthesis  as  taken 
up  in  this  work  divides  itself  naturally  into  two  parts,  first 
the  securing  of  a benzene  derivative  with  two  hydroxyls  symme- 
trically placed  with  respect  to  a side  chain,  and  second  the 
conversion  of  that  side  chaixi  into  a propyl  group. 

To  accomplish  the  first  step  the  work  of  h.  Cornelius 

6 7 

and  H.  von  Pechmann  , L.  Wolman  and  K von  Peckman  and  of 

8 

I).  S.  Jordan  on  the  preparation  of  3> 5 > dihydroxy  phenyl  ace- 
tic acid  was  followed. 

The  starting  point  was  diethyl  acetone  aicarboxylate  (A) 
prepared  'ey  the  treatment  of  citric  acid  wit  a 2 0 per  cent 
fuming  sulfuric  acid  to  give  one  acetone  dicarb oxylate  wnich 
v;as  esterifiea  with  etnyi  alconol  and  dry  HC1.  This  is  the 
method  descrioed  'ey  Wi  list  fitter  and  Pfannemstiei  . 

Two  methods  for  condensing  the  dietnyl  acetone  dicar- 
boxy  late  into  a dinjalroxy  benzene  derivative  nave  seen  des- 
cribed and  ooth  were  tried.  The  first  method  is  tn.au  of 
e 

13.  S.  Jerdan  in  which  magnesium  powder  is  used  as  trie  condens- 
ing agent  with  ethyl  chloroacetate  as  a catalyst.  The  product 
secured  by  this  condensation  is  diethyl  hydrogen  ore  in 
tricarboxylate  (B).  This  reaction  ran  very  smoothly  and  littae 


-5- 


COOCaHs  (B) 

difficulty  was  encountered  in  the  purification,  out  the  yield 
was  too  low  to  warrant  its  use  in  this  problem. 

The  second  method  was  first  used  by  Cornelius  and  von 

, 8 

Pechman  in  IS06  and  later  L .ed  by  I).  1.  Jordan.  It  con- 
sists in  the  use  of  about  1 per  cent  of  Ha  as  a condensing 
agent  and  the  compound  formed  in  this  case  is  triethyl  ore  in 
tricar  coxy  late  (C)’ 

CK3CCOC3EB 
/'N  C00C3H5 
ho  on 

COOC3H5  (c) 

This  reaction,  according  bo  von  Pechman  can  oe  explained 
as  foiiows. 


(A) 

COOC3H5  COOCsKb 

1 1 

Cha  haC 

I 

C = 0 

I 

CKa 


COOC3H5  COOCsHb 

I I 

C h 1 ^ 


c = 0 

I 

Ha-  C-ii 


’OC  ah  6 


COOC3H5 


COOC2K6 

I 

CHa 
C 

/ \ 

HC  C-COOCaHji 

-»  II  I 

ho-C  C-O-H 

\f  „ (Cl 

^COOCahs 


-6- 


Along  with,  the  triethyl  orcin  tricarboxylate  (C)  a con- 
siderable quantity  of  by-products  are  formed  which  can  be 
best  separated  from  C by  washing  its  ether  solution  with  di- 
lute sodium  caroonate  and  acidifying  the  sodium  carbonate 
solution.  Most  of  the  by-products  precipitated  by  this  acid- 
ification appear  to  be  partially  hydrolyzed  products  from  C. 

/ 

In  some  cases  a small  quantity  of  a compound  that  agrees  in 

10 

melting  point  with  Jordan's  lactone  can  be  isolated  from  this 
precipitate.  Jerdan’s  lactone  is  the  principal  product  when 
this  condensation  is  carried  out  in  benzene  solution. 

It  was  found  advisable  to  proceed  with  the  next  step 
without  purifying  the  triethyl  orcin  tricarboxylate.  first 
because  both  the  washing  with  sodium  carbonate  and  the  crystal- 
lization result  in  the  loss  of  considerable  pure  product,  and 
second,  since  the  next  step  is  complete  Hydrolysis  the  partial- 
ly hydrolyzed  compounds  which  are  present  as  oy-pooducts  yield 
the  same  compound  as  the  pure  triethyl  orcin  tricarboxylate . 
Both  unchanged  diethyl  acetone  dicaroo^ylate  and  Jerdan’s 
lactone,  drop  out  in  the  course  of  the  next  few  steps. 

If  the  hycLroijrsis  is  carried  out  carefully  a rather  large 

number  of  partially  hydrolyzed  products  may  oe  secured  from 

8 

the  triethyl  orcin  tricarboxylate  . When  subjected  to  vigorous 
hydrolysis  however  the  compound  loses  not  only  tnree  molecules 
of  alconoi  but  also  two  molecules  of  carbon  dioxide,  giving 
2, 5 > dihydro  xy  acetic  acid.  (D)  This  is  what  'would  be  ex- 
pected from  the  usual  instability  Ox'  carboxj^l  groups  attqcned 


to  a polyhydroxy  phenol.  Trie  original  method  of  von  Pechioan 
involving  fusion  with  50  per  cent  KOH  was  found  most  satis- 
factory for  this  hydrolysis  though  it  would  seem,  at  first 
thought,  entirely  too  vigorous  a treatment  for  trie  synthesis 
of  so  delicate  a compound  as  dihydroxy  phenyl  acetic  acid. 

The  original  method  devised  by  von  Pecinnan  for  purifying 


the  hydroxy  acetic  acid  (D)  involving  an  ether  extraction  and 
purification  thru  the  lead  salt  was  not  practicable  for  this 
problem  where  relatively  large  quantities  of  the  compound  we re 
desired.  Wot  only  is  the  process  too  involved  for  large  quan- 
tities but  the  hydroxy  phenyl  acetic  acid  is  so  soluble  in 
water  that  even  7 or  3 extractions  fail  to  give  anything  aike 
a quantitative  separation.  Enough  of  the  compound  was  puri- 
fied 03  unis  method  however  to  identify  it  as  5> dihydroxy 
phenyl  acetic  acid. 

It  was  desirable  to  convert  the  hyaroxy  acid  into  some 
compound  less  water  soluble  in  order  to  make  its  isolation 


easier  . xhe  natural  derivative  was  of  course  trie  dimethcxy 
ellier  wnich.  had  trie  added  advantage  of  being  more  staole  than 
o;ie  free  hydroxy  acid.  Its  preparation  was  made  easy  03  regu- 
lating file  amount  of  alkali  used  in  the  hydrolysis  in  such  a 


way  that  the  methylation  could  be  carried  out  by  simply  adding 
dimethyl  sulfate  to  the  cruae  saponification  mixture. 

x)ie  1 ree  acid  was  desired,  so  the  methyl  ester  of  the  di- 
me thoxy  phenyl  acetic  acid,  produced  during  the  methylation, 
was  saponified  with  KOH  and  the  free  acid  liberated  with  HC1 . 


rs 


— o— 


Up  to  this  point  none  of  the  by-products  formed  in  the  sodium 
condensation  had  been  removed.  It  was  at  first  thougnt  advis- 
able to  separate  them  at  this  point  oy  taking  advantage  of  the 
solubility  of  the  dimethoxy  phenyl  acetic  acid  in  dilute  sodium 
carbonate.  Jerdan’s  lactone  would  be  changed  to  trimethoxy 
phloroglucinol  at  this  point  and  be  insoluble*  Experience 
showed  however  that  this  was  not  necessary  as  these  impurities 
were  eliminated  during  crystallization.  The  compound  was  easii; 
isolated  by  salting  it  out  from  the  strongly  acidified  me  thy la- 
ri on  mixture  ana  recrys tallizing  it.  Its  neutral  equivalent 
checked  the  theoretical. 

The  5> dimethoxy  phenyl  acetic  acid  thus  prepared  becomes 
the  starting  point  for  the  second  part  of  the  problem,  namely 
the  changing  of  the  side  chain  into  a propyl  group.  In  order 

to  introduce  another  carbon  into  the  siae  chain  advantage  is 

1 1 

taken  of  the  work  of  Clibbins  and  Kiernstein  on  the  formation 
of  chloroket ones  from  acid  chlorides  and  diazo  methane.  The 
acid  chloride  is  prepared  by  the  action  of  thienyl  chloride  on 
the  dimethoxy  phenyl  acetic  acid.  This  acid  chloride  in  dry 
ether  solution  is  then  treated  with  a molecular  quantity  of 
diazo  methane  also  in  dry  ether  solution.  The  product  thus 
formed  is  5 > dimethoxy  phenyl  cnloroacetone . (E) 


Glia  COCKs  Cl 


* 


-9' 


The  difficulty  encountered  at  this  point  is  due  to  the 
ease  with  which  small  Quantities  oi  alcohol  present  in  the 
diazo  methane  solution  react  with  the  acid  chloride  to  give 
the  ester.  Thus  if  the  diazo  methane  is  prepared  by  the  method 
of  von  Pechman,  by  adding  KOH  in  absolute  methyl  alcohol  to 
nitroso  methyl  urethane  in  ether  and  distilling  off  the  ether 
solution  of  diazo  methane,  enough  alcohol  is  carried  over  to 
prevent  the  formation  of  even  a trace  of  the  chloroketone.  If 
absolute  butyl  alcohol  is  substituted  for  the  methyl  aiconoi 
and  a stream  of  nitrogen  -used  to  carry  over  the  diazo  methane, 
a small  quantity  of  the  chloroketone  can  be  isolated,  but  the 
butyl  ester  is  the  principal  product.  The  method  of  Staudiiiger 

13 

and  Kaupfer  used  in  the  original  work  of  Clibbins  and 
Niernstein  is  probably  the  most/  desirable  for  the  preparation 
of  diazo  methane  for  this  reaction. 

The  chloroketone  is  then  reduced  to  the  dimethoxy  phenyl 

13 

propane  the  metnod  of  Clemnenson  using  zinc  amalgam  and 
hydrochloric  acid. 

Divarin  itself  is  secured  by  hydrolyzing  the  methyl  groups 
with  hydriodic  acid  to  give  the  >, 5, dihydroxy  phenyl  propane. 


-10- 


IV  EXPERIMENTAL 

A.  Triethyl  Ore in  Tricar boxy late. 

150  g.  of  diethyl  acetone  dicarboxylate  are  placed  in  a 

flask  equipped  with  a reflux  condenser  and  an  efficient  mecnan-' 

ical  stirrer.  This  is  heated  to  140  J on  an  oil  oath  and  1*5 

g.  of  finely  chipped  sodium  is  added  slowly.  The  material 

is  kept  at  140  with  continuous  stirring  for  1 1/2  nours  at 

the  end  of  which  time  amother  1*5  g«  of  sodium  is  added.  The 

0 

temperature  is  kept  at  140  and  the  stirring  continued  until 
a rather  heavy  yellow  flocculeht  precipitate  separates  out. 

This  occurs  at  trie  end  of  about  another  1 l/2  hours.  Addi- 
tional heating  is  not  harmful.  The  mat ar  lax  is  poured  into 
a beaker  and  solidifies  on  standing.  The  crude  product  (about 
145  g.  ) is  centifuged  or  pressed  free  from  adhering  liquid, 
digested  with  a little  cola  dilute  sulfuric  acid  and  dissolved 
in  ether.  The  ether  solution  is  washed  with  a xittie  dilute 
sodium  car oonate  solution.  Care  must  be  exercised  at  this 
point  as  the  triethyl  orcin  tricarooxylate  is  quite  soluble 
in  sodium  carbonate  solution.  The  washing  should  oe  stopped 
as  soon  as  tne  wash  water  is  no  longer  colored  green.  Trie 
ether  solution  is  dried  with  calcium  chloride  axid  the  ether 
evaporated.  Trie  trimethyl  compound  may  be  recrystallized 
from  petroleum  ether  or  dilute  alcohol.  iHe  petroleum  ether 
product  has  a slight  cream  color  while  that  from  alcohol  is 
pure  white.  Considerable  difficulty  is  experienced  with  alco- 


-11- 


hoi  however  due  to  the  tendency  of  the  material  to  separate  as 

an  oil*  One  crystallization  from  alcohol  yielas  the  triethyl  | 

0 ! 

ore  in  tricarboxylate  as  matted  white  needles  melting  < 

13.  3, 5,Dihydr  xy  nyl  Acetic  Acid. 

20  g.  of  the  crude  sodium  condensation  product,  pressea 
free  from  liquid,  is  added  to  40  g.  of  potassium  hydroxide  dis- 
solved in  an  equal  weight  of  water.  This  mixture  is  heated  in 
a nickel  crucible  as  strongly  as  frothing  will  permit  for  about 
15-20  minutes  or  until  a drop  on  the  end  of  ^ glass  rod  solidi- 
fies on  cooling.  Most  of  the  alcohol  comes  off  during  the 
first  5 minutes  heating  as  is  indicated  by  the  inf lapmability 
of  the  gas  during  this  period.  40  cc.  of  water  are  adaea 
before  the  material  has  cooled  enough  to  solidify*  The  solu- 
tion thus  prepared  is  used  for  trie  preparation  of  3>  5 > dimethoxy 
phenyl  acetic  acid  which  is  described  later. 

If  the  pure  dihydroxy  acid  is  desired  decompose  the  fusion 
product  with  dilute  sulfuric  acid  and  extract  repeatedly  with 
ether.  The  residue  from  the  last  portions  of  ether  is  almost 
pure  dihydroxy  phenyl  acetic  acid.  The  residue  secured  by 
evaporating  the ether  is  dissolved  in  a considerable  quantity 
of  water,  digested  from  1 to  3 hours  with  an  excess  01  lead 
carbonate,  and  filtered  boiling  hot.  On  cooling  the  filtrate 
the  lead  salt  separates  out  in  white  needles.  Yield,  from  puri- 
fied triethyl  ore  in  tricar boxy late,  about  40  per  cent. 


-12- 


C.  3,3,Dimethoxy  Phenyl  Acetic  Acid. 

The  material  from  7 of  the  preceding  fusions  (i.e.  from 
130  g.  of  diethyl  acetone  dicarboxylate ) is  combined  and  placed 
in  a 2 liter  flask  equipped  with  a stirrer  and  a reflux  con- 
denser. 295  g.  of  dimethyl  sulfate  is  added  in  small  par-cions 
with  vigorous  stirring.  The  addition  should  require  about  an 
hour  and  the  heat  of  reaction  is  sufficient  to  xeep  tne  temper- 
ature at  about  7QJ  - So"*.  At  the  end  of  2 hours  stirring  70  g* 
additional  dimethyl  sulfate  with  30  g*  of  potassium  hydroxide 
in  an  equal  weignt  of  water  is  added  slowly.  The  mixture  is 
stirred  for  another  2-3  hours  at  the  end  of  wnicn  time  a i^er 
resembling  whipped  gelatin  forms  on  top  of  the  solution. 

200  cc.  of  30  per  cent  potassium  nydroxiue  is  added  and  the 

r.  0 

mixture  stirred  on  a water  bath  at  about  03  for  3 hours  by  the 
end  of  which  time  the  water  insoluble  layer  has  disappeared. 

A rather  heavy  precipitate  of  salt  has  formed  however.  The 
saponified  mixture  is  cooled  and,  without  filtering,  aciuified 
with  hydrochloric  acid.  A rather  heavy  flocculent  precipitate 
comes  down  with  the  salt  and  continues  to  increase  as  more  acid 
is  added  until  a considerable  excess  of  hydrochloric  has  been 
added.  The  precipitate  is  filtered,  sucked  dry,  and  trie  dimeth- 
oxy  acid  extracted  from  the  salt  with  ether.  The  test  yield  is 
secured  by  extracting  the  dry  salt  several  times  and  then  dis- 
solving it  in  water  and  extracting  the  balance  of  the  acid  from 
the  solution.  The  ether  residues  are  re crystallized  first  from 
benzene  and  then  from  a rather  large  volume  of  petroleum  ether. 


• W \ 1 

-13- 

Yield  about  20  per  cent  of  the  theory  based  on  the  diethyl 

acetone  dicarboxylate . If  very  pure  material  is  desired  it  can 

be  secured  by  recrystallising  from  hot  water.  Crystallizes 

o o 

from  water  in  long  white  needles  melting  at  100.5-101.5  » 


-14— 


V CONCLUSIONS 

1.  5 1 dimethoxy  phenyl  acetic  acid  can  be 
prepared  in  yields  sufficiently  large  t o warrant  its 
use  as  a starting  point  for  the  synthesis  of  symme- 
trical dihydroxy  benzene  derivatives.  It  is  superior 
for  this  purpose  to  the  dihydroxy  phenyl  acetic  acid. 

2.  The  work  is  being  continued  with  every  indi- 
cation that  a successful  conclusion  will  be  reached. 


-13- 


VI  BIBLIOGRAPHY 


1.  Oswald  Hesse 


J.  prakt . Che  in.  Si . 22-96* 


2.  Zopf 

5*  Johnson  and  Hodge 
4.  Adolf  Sonn 
5*  F.  W.  Semmler 
H.  Thoms 

6.  Cornelius  and  von  Pechman 
7*  Wolman  ana  von  Pecnman 


Ann.  Chem.  1£Q,  335* 
Flechtenstoffe,  1907,  C.  251. 

J.  Am.  Chem.  Sac.,  7)5 . 1014-23* 
Ber.  14,  773~4-  (1921) 

Ber.  41,  2556. 

Ber.  J&,  3449* 

Ber.  H,  1447  ( 1886  ) 

Ber.  11,  2014  (1698) 

J.  Chem.  Soc.,  21,  808  (1899) 


8.  D.  S.  Jerdan 

9.  Willst&tter  and  Pfannenst ieAnn.  422 . 5 (1921) 


10.  I).  8.  Jerdan 

11.  Clibcens  and  Jiernstein 

12.  Staudinger  and  Kupfer. 

13.  Clemmensen 


J.  Chem.  Soc.,  21,  1106  (1897) 

J.  Chem.  80c.,  107.  1491-2  (1913) 
Ber.  41,  50  1 (1912) 

Orig.  Com.  8th  Intern.  Congr. 
Appl.  Chem.  1,  68-76. 

Ber.  42,  31-63 
Ber.  47 . 681-7. 


